Four organotin(IV) carboxylate complexes; (CH)SnL (), CHSnL (), (CH)SnL () and (CH)SnL () are synthesized by the condensation reaction of organotin(IV) chlorides with sodium-4-chloro-2-methylphenoxyacetate (). The FT-IR spectra suggested bridging/chelating bidentate coordination of the ligand to the tin atom. Single-crystal XRD analysis authenticated the FT-IR findings for and . The NMR study has shown no significant differences in the signals of the free and coordinated ligand except for absence of a proton and up-filed/down-field shift of the C signal of the carboxyl group in the spectra. Complexes - have shown better enzyme inhibition, antioxidant, antimicrobial, and anticancer activities compared to the free ligand acid. Complex was the most active inhibitor of AChE, BChE, α-glucosidase and α-amylase with IC values of 43.76, 102.39, 232.71 and 91.84 µg/mL, respectively. Additionally, with IC values of 7.52 and 8.77 µg/mL in the DPPH and ABTS assays, respectively was better antioxidant than the standard. Complex was the most efficient inhibitor of MAO-B and COX-2 enzymes with IC values of 106.99 and 12.98 µg/mL, respectively, while (IC = 38.97 µg/mL) has shown the highest 5-LOX inhibition potential. Complexes - with IC values in the range 237.51-168.35 µg/mL have shown better antileishmanial activity than (IC = 277.57 µg/mL). The compounds showed good to potent antiproliferative activity in malignant glioma U87 cells with IC values in the range 12.54 ± 0.05 to 37.65 ± 0.04 µg/mL. Antimicrobial activities have shown promising results for the compounds compared to the standards in some cases.

1,3,4-Oxadiazole-based heterocyclic analogs (3a-3m) were synthesized cyclization of Schiff bases with substituted aldehydes in the presence of bromine and acetic acid. The structural clarification of synthesized molecules was carried out with various spectroscopic techniques such as FT-IR,H and C-NMR, UV-visible spectroscopy, and mass spectrometry. antifungal activity was performed against , and and analogs 3g, 3i, and 3m showed potent MIC at 200 µg/ml and excellent ZOI measurements of 17-21 nm. The cell viability on Huh7 for lead molecules 3g, 3i, and 3m was found to be 99.5%, 92.3%, and 86.9% at 20, 10, and 20 μM, respectively. The antioxidant activity of molecules 3 g, 3i, and 3 m was estimated and exhibited great IC values of 0.104 ± 0.021, 0.145 ± 0.05, and 0.165 ± 0.018 μg/mL with DPPH and 0.107 ± 0.04, 0.191 ± 0.12, and 0.106 ± 0.08 with HO, respectively. The binding interaction mode for the lead molecules was also carried out with Ct-DNA using the absorption, emission, CV, CD, and Time resolve fluorescence techniques. The results showed good binding constant (K) values of 9.1 × 10, 9.94 × 10, and 9.32 × 10 M for 3g, 3i, and 3m, respectively. TD-DFT study of compounds 3g, 3i, and 3m was done to find out HOMO/LUMO energy levels, surface study of the molecular electrostatic potential, Mulliken population analysis, and natural bond orbitals showing the linkages between the donors and acceptors.Molecular docking of three lead analogs with PDB ID: 1BNA and molecular modelling of compounds 3g, 3i, and 3m with CYP51 protein (PDB ID: 5FSA) were carried out.Communicated by Ramaswamy H. Sarma.

The present study explores the conformational dynamics of the membrane protein of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) within the Endoplasmic Reticulum-Golgi Intermediate Compartment (ERGIC) complex using an all-atomistic molecular dynamics simulation approach. Significant structural changes were observed in the N-terminal, C-terminal, transmembrane, and beta-sheet sandwich domains of the MERS-CoV membrane protein. This study also highlights the structural similarities between the MERS-CoV and the SARS-CoV-2 membrane proteins, particularly in how both exhibit a distinct kink in the transmembrane helix caused by aromatic residue-lipid interactions. A structural expansion below the transmembrane and above the beta-sheet sandwich domain within the dimer was observed in all the M-proteins. This site on the beta-sheet sandwich domains near the C-terminal end could serve as a potential drug-binding site. Notably, a stable helical structure was identified in the C-terminal domain of the MERS-CoV membrane protein, whereas a proper secondary structural conformation was not observed in the SARS-CoV-2 membrane protein. Further, the SARS-CoV-2 membrane protein exhibited stronger binding to the lipid bilayer than the MERS-CoV, indicating its greater structural stability within the ERGIC complex. The structural similarity between the membrane protein of MERS-CoV and SARS-CoV-2 suggests the feasibility of employing a common inhibitor against these beta-coronaviruses. Furthermore, this analysis enhances our understanding of the membrane protein's interactions with proteins and lipids, paving the way for therapeutic developments against these viruses.

Methicillin-resistant (MRSA), a major cause of fatalities due to Antimicrobial Resistance (AMR), can act as an opportunistic pathogen despite being part of the normal human flora. MRSA infections, such as skin infections, pneumonia, sepsis, and surgical site infections, have risen significantly, with bloodstream infection cases increasing from 21% in 2016 to 35% in 2020. This surge has prompted research into alternative treatments like nanomaterials, photodynamic therapy, antimicrobial peptides (AMPs), and essential oils (EOs). AMPs and EOs have shown higher success rates compared to other alternatives, gaining significant attention for their effectiveness against MRSA. In this perspective, we have created a database for peptides and EOs that have been discovered to treat MRSA. Manual data curation was done to get related information on each of the anti-MRSA EOs and AMPs from the PubMed articles. This led to the curation of 1789 peptides (1029 unique) and 863 EOs (671 unique) that have been reported against MRSA. This was followed by database creation and the development of tools for sequence analysis and determination of physiochemical properties. This resource has been named 'The Anti-MRSA Resource' or 'TAMRSAR' which we believe will aid in future drug development efforts to combat the diseases caused by MRSA. The database is accessible on any web browser at the URL: https://bblserver.org.in/tamrsar/.

The COVID-19 pandemic posed a threat to global society. Delta and Omicron are concerning variants due to the risk of increasing human-to-human transmissibility and immune evasion. This study aims to evaluate the binding ability of these variants toward the angiotensin-converting enzyme 2 receptor and antibodies using a computational approach. The receptor-binding domain (RBD) of the two variants was created by CHARMM-GUI and then docked to the hACE2 receptor and two antibodies (REGN10933 and REGN10987). These complexes were also subjected to molecular dynamics simulation within 100 ns. As a result, the two variants, Omicron and Delta, exhibited stronger interaction with the hACE2 receptor than the wild type. The mutations in the RBD region also facilitated the virus's escape from antibody neutralization.

The combination of clopidogrel and acetylsalicylic acid is the standard treatment for atherosclerotic cardiovascular disease. Nonetheless, there is a pressing need for more potent P2Y receptor inhibitors with quicker onset, especially for early intervention in acute myocardial infarction. Integrating computational modeling, i.e. pharmacophore modeling, molecular docking, and dynamics, with empirical data guides the development of effective antiplatelet therapies. This multidisciplinary study employs computational modeling and experimental analysis, demonstrating significant inhibition of P2Y activity by two NCI compounds namely: NSC380324 and NSC618163. Both NSC380324 and NSC618163 exhibited a platelet reactivity index (%PRI) of 30.0% and 34.0%, respectively compared to cangrelor that demonstrated superior activity, with a %PRI of 11.0% in platelet vasodilator-stimulated phosphoprotein (VASP) assay. Molecular docking simulations show strong binding affinities of both compounds, along with strong binding interactions at the P2Y binding site. Importantly, molecular dynamics simulations highlight the influence of receptor dynamics on practical efficacy, suggesting that NSC380324, a promising P2Y antagonists indicated by its excellent stability profiles at the binding pocket of P2Y, its hydrogen-bond interactions occupancies and the average MM-PBSA total binding energy of -38.17 kcal/mol, require further structural optimization and studies to realize their full potential for clinical application.

RbgA (ribosome biogenesis GTPase A) is involved in the maturation of later stages of the 50S ribosomal subunit by associating with the 45S ribosomal subunit. However, this binding relies on the specific nucleotide-bound state of RbgA-GTP-bound state is more favorable compared GDP-bound state, attributed to the conformational variations between those states. Therefore, to explore the conformational changes of RbgA, all-atom MD simulations of RbgA were carried out under various nucleotide bound states (GDP, GTP, GTP-Mg and GMPPNP-Mg). The analysis of overall conformational changes using RMSD and Rg revealed sharp equilibration for GTP-Mg and GMPPNP-Mg nucleotide bound systems. Investigating internal variations through RMSF and cluster analyses helps us to identify the functionally important regions and nucleotide driven conformational variations that may stabilize/destabilize the RbgA-ribosome association. In addition, the construction and analyses of the dynamical protein contact network from the simulated trajectory reveal the nucleotide dependent allosteric connections between the nucleotide binding site and the rRNA interacting residues. Furthermore, the visualization followed by the dynamical distance calculations exhibited the possible role of Mg in assisting GTP hydrolysis, such as (i) positioning the Asp150 of the switch-I (Sw-I) loop residue in a catalytically feasible configuration and (ii) stabilizing the solvated water molecules at the active-site through Mg coordination. The results of our study can be used to design better chemical agents to regulate ribosome biogenesis through modulation of the function of the RbgA.

Chromosomal rearrangements are common oncogenic events in Non-Small Cell Lung Cancer. An example is the fusion of the ROS1 kinase domain with extracellular receptors. Although the fusion leads to a target that is druggable with multi-kinase inhibitors, several reports indicate the emergence of point mutations leading to drug resistance. Although these mutations are often located in the ATP binding pocket, a subset of them is neighboring the pocket without a direct effect on drug binding. Due to the clinical impact of these allosteric mutations, there is an urge to identify the mechanism of resistance and characterize the pocket for further drug design studies. This study aimed to unravel the resistance mechanism of L1982F and S1986F/Y mutations. The variants were modeled and simulated using classical Molecular Dynamics simulations and accessed for their conformational flexibility. Our results indicate a direct effect of these allosteric mutants in the binding pocket volume with an indication of the G-loop playing a central role.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the formation of Lewy bodies, which are primarily composed of misfolded α-Synuclein (α-Syn). DJ-1 is a crucial protein involved in the correct folding of α-Syn, and mutations impairing its function are associated with the onset of PD. One such mutation, the L166P substitution in DJ-1, which has been linked to early-onset PD and results in the loss of DJ-1's homodimer structure. Recent studies have shown the presence of DJ-1 in Lewy bodies, but its interaction with α-Syn is unknown. Therefore, in this study, we investigated the interaction between α-Syn and DJ-1 in both its wild-type (wDJ-1: homodimer) and L166P mutant (mDJ-1: monomer) forms using molecular dynamics simulation. Our results indicated that α-Syn binds more tightly to mDJ-1 than to wDJ-1. Gibbs free energy landscape analysis showed that the bonded α-Syn to mDJ-1 complex represents a stable conformation, whereas only a partial connection of α-Syn to wDJ-1 was observed. Generally, it appears that the monomer form of DJ-1 resulting from the L166P mutation can form a stable complex with α-Syn, potentially intensifying the formation of Lewy bodies. Thus, the identification of aggregated α-Syn with DJ-1 may serve as a potential biomarker for PD.

Cryptosporidiosis is an infection induced by the single-celled protozoan Cryptosporidium parasite. This parasite commonly infects the intestines of humans and animals, leading to gastrointestinal symptoms such as diarrhea, stomach cramps, nausea, and vomiting. Cryptopain protein, a type of cysteine protease found in the genome of plays an important role in cell invasion and its survival. In this study, we mainly focused on the structural validation and reliability of docking aspects of the Cryptopain protein of . The best-modeled structure of Cryptopain protein was run in a water environment through a 200 ns Molecular Dynamics (MD) simulation study. We employed a covalent docking scheme to screen suitable inhibitors against our target protein. Furthermore, the reliability of the binding mode for the best possible inhibitors was validated at a 100 ns time frame through a complex MD simulation study. From docking and simulation studies, we found Z3952175270 as a possible inhibitor on the basis of docking score and binding affinity for the possible binding site in the Cryptopain protein. Our findings highlight the potential of targeting Cryptopain protein with specific inhibitors, which could pave the way for the development of novel therapeutic strategies against cryptosporidiosis. This work contributes to the field by providing a deeper understanding of the molecular interactions involved in Cryptopain inhibition, potentially leading to effective treatments for a disease that significantly impacts public health, particularly in immunocompromised individuals and in areas with limited access to clean water.

The increasing incidence of bacterial infections has led to rise in antimicrobial resistance (AMR), a significant concern in public health across the globe. Henceforth, there is an urgency to address the AMR catastrophe, including developing new antibiotics, promoting the appropriate use of existing antibiotics, and investing more in research and development. Development of potent antibiotic derivatives is the call of the day. Herein, we designed a novel series of ciprofloxacin derivatives joined with sulfa-drugs (CIS1-15) and screened them against Dihydropteroate synthase and DNA gyrase through molecular docking and molecular dynamics (MD) simulations. MD simulation displayed the dynamics stability of the top-ranked docked poses, while flexibility and low-energy conformational states of these complexes the dynamics stability of the top-ranked docked poses. In contrast, the flexibility and low-energy conformational states of these complexes were inferred using principal component analysis and free energy landscape analysis. The derivatives of CIS2, CIS3, CIS5, CIS6, CIS8 and CIS15 showed strong binding affinity against both the target receptors with retention of conformational stability during MD. Pre- and post-MD snapshots show the crucial role of Arg63, Arg1072, Gly1073, and Val71 residues in the recognition of ciprofloxacin derivatives. Our in-depth structural study advocates that CIS5 and CIS6 could effectively inhibit DNA gyrase and dihydropteroate synthase. Overall, our comprehensive computational approach employed in this study establishes a benchmark for the identification of physiologically significant small molecules against emerging drug targets to design drugs based on their structure and locating potent drug-like molecules with promise for antibacterial potential.

The recent spread of SARS-CoV-2 has led to serious concerns about newly emerging infectious coronaviruses. Drug repurposing is a practical method for rapid development of antiviral agents. The viral spike protein of SARS-CoV-2 binds to its major receptor ACE2 to promote membrane fusion. Following the entry process, the spike protein is further activated by cellular proteases such as TMPRSS2 and Furin to promote viral entry into human cells. A crucial factor in preventing SARS-CoV-2 from entering target cells using HIV-1 fusion inhibitors is the similarity between the fusion mechanisms of SARS-CoV-2 and HIV-1. In this investigation, the HIV-1 fusion inhibitors CMK, Luteolin, and Naphthofluorescein were selected to understand the molecular mode of interactions and binding energy of Furin with these experimental inhibitors. The binding affinity of the three inhibitors with Furin was verified by molecular docking studies. The docking scores of CMK, Luteolin and Naphthofluorescein are -7.4 kcal/mol, -9.3 kcal/mol, and -10.7 kcal/mol, respectively. Therefore, these compounds were subjected to MD, drug-likeness, ADMET, and MM-PBSA analysis. According to the results of a 200 ns MD simulation, all tested compounds show stability with the complex and can be employed as promising inhibitors targeting SARS-CoV-2 Furin protease. In addition, pharmacokinetic analysis revealed that these compounds possess favorable drug-likeness properties. Thus, this study of Furin inhibitors helps in the evaluation of these compounds for use as novel drugs against SARS-CoV-2.

The quest for sustainable solutions to plastic pollution has driven research into plastic-degrading enzymes, offering promising avenues for polymer recycling applications. However, enzymes derived from natural sources often exhibit suboptimal thermostability, hindering their industrial viability. Protein engineering techniques have emerged as a powerful approach to enhance the desired properties of these biocatalysts. This study aims to conduct a comprehensive analysis of the thermostability of PETase (VpPETase) through an integrated computational approach encompassing homology modeling, site-specific molecular docking, molecular dynamics (MD) simulations, and comparative evaluation of a single-point mutation (V195F) against the wild-type enzyme. Homology modeling was used to predict VpPETase model using multiple templates. Model quality was rigorously assessed using Ramachandran plot analysis, ProSA, Verify 3D, and ERRAT. Molecular docking elucidated the catalytic region comprising residues His149, Asp117, and Ser71, while highlighting the pivotal roles of His149, Tyr1, and Ser71 in substrate binding affinity. MD simulations at various temperatures revealed higher stability at 313.15 K over a 100 ns trajectory, as evidenced by analyses of root-mean-square deviation (RMSD), radius of gyration (Rg), solvent-accessible surface area (SASA), hydrogen bonding, and root-mean-square fluctuation (RMSF). The V195F mutant exhibited a slight increase in stability compared to wild-type. While this study provides valuable insights into the thermostability of VpPETase, further investigations, including experimental validation of thermostability enhancements and characterization, are warranted to fully exploit the potential of this enzyme for industrial applications in plastic recycling.

Tryptophan catabolism is a central pathway in many cancers, serving to sustain an immunosuppressive microenvironment. The key enzymes involved in this tryptophan metabolism such as indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are reported as promising novel targets in cancer immunotherapy. IDO1 and TDO overexpression in TNBC cells promote resistance to cell death, proliferation, invasion, and metastasis. To date, there are no clinically available small-molecule inhibitors that target these enzymes. Navoximod, a reliable dual-specific inhibitor, resulted in poor bioavailability and modest efficacy in clinical trials restricts its utility. This situation urges the development of a potent drug-like candidate against these key enzymes. A total of 1574 natural compounds were proclaimed and subjected to ADME screening. Subsequently, the resultant compounds were attributed to hierarchical molecular docking and MM-GBSA validation. Ultimately, re-scoring with the aid of combined machine learning algorithms resulted six lead compounds. Captivatingly, NPACT00380 exhibited maximum interaction among the lead compounds. In addition, the scaffold analysis also highlighted that the chromanone moiety of the hit compound boasts anti-cancer activity against breast cancer cell lines. The reliability of the results was corroborated through a rigorous 100 ns molecular dynamics simulation using the parameters including RMSD, PCA and FEL analysis. In light of these findings, it is presumed that the proposed compound exhibits significant inhibitory activity. As a result, we speculate that further optimisation of NPACT00380 could be beneficial for the treatment and management of TNBC.

Alzheimer's disease is one of the most complex neurological disorders and millions of people are suffering from this disease all over the world. In the past two decades acetylcholinesterase (AChE) has been the most explored pathological hallmark. The generation of potent AChE inhibitors has grown as a rapid pathological tool for the efficacious treatment of the disease. Hence, AChE enzyme is extensively explored as a drug discovery tool for the development of potent therapeutics. We have used chromone derivatives with known biological activities for developing a Gaussian field-based 3D QSAR pharmacophore model using PHASE module of Schrodinger with statistically significant R and Q values of 0.92 and 0.9209, respectively. ChEMBL and MCULE databases were screened using the best pharmacophore hypothesis model (AAHHRR_4) with features of two hydrogen bond acceptors (A1, A2), two hydrophobic regions (H1, H2), and two aromatic regions (R1, R2). These were subjected to structure-based virtual screening using extra precision, MM/GBSA and ADME calculations for calculating the binding free energies and pharmacokinetic properties, respectively. Subsequently, two hit molecules i.e. and were identified. The leads exhibited higher docking score (-8.859 and -9.984 kcal/mol) and ΔG (-57.63 and -56.45 kcal/mol) as compared to the reference (ΔG= -53.79 kcal/mol). MD simulation study exhibited stable interactions with the binding free energy (ΔG) of -27.29 and -21.26 kcal/mol for CHEMBL1319989 and MCULE-2246633290, respectively. So, the generated pharmacophore model may be considered as a valuable tool for the development of potent AChE inhibitors for the treatment of AD.

A series of 2,6-di(pyrazine-2-yl)pyridine (dppy) ligands - of varying substituents of different electronic nature (-NMe, -OMe,-Me, and -Cl) in the 4-position of the pyridine moiety has been designed and synthesized to study the binding behavior of the dppy ligands towards Bovine Serum Albumin (BSA), a low-cost serum albumin protein. The interaction between ligands and BSA has been studied using UV-Visible and fluorescence spectroscopy and molecular docking studies. The fluorescence of BSA was found to be quenched in the presence of all the ligands , in which ligand , having the most electron donating group NMe exhibits the maximum binding affinity towards BSA. The interaction between ligands and BSA was found to be static and spontaneous in nature. Further, the effect of substituents on the photophysical, thermal, and electrochemical properties of the dppy ligands has also been studied. Structure optimization and theoretical studies have been conducted to acquire a deeper understanding of the ligands' nature. The trend of the energy gaps between the HOMO and the LUMO of the synthesized ligands , calculated from the electrochemical analysis, has been reflected in the theoretical observations. Moreover, the ligands were also tested against different bacterial and fungal strains, and ligands containing electron-donating-NMe and-OMe groups were quite active in both bacterial and fungal studies. The ligand , having the-CH group, showed moderate activity against fungal strains.

Public health is seriously threatened by the highly pathogenic zoonotic Nipah virus (NIV). Since no effective medicines or vaccines exist, it is imperative to investigate potential therapeutic molecules against NIV. In this research, we concentrated on the G-glycoprotein of NIV as a potential therapeutic target. From seven medicinal plants renowned for their antiviral efficacy against NIV, we created a chemical library with 80 phytocompounds. The compounds were subjected to molecular docking, drug-likeliness properties, and toxicity analysis (ADMET). Based on good docking scores and ADMET properties, we opted for two compounds-Phyllnirurin (CID: 179963) and Diosgenin (CID: 99474). Post-docking analysis and molecular dynamics simulations validated the interactions and stability of the complexes formed between the protein and ligands. Finally, network pharmacology analysis demonstrates that these compounds interact with a wide range of host proteins. Therefore, these two phytocompounds in terms of lead candidates, have the potential to be key players in developing therapies against the Nipah virus, and future experimental validation is required.

Antimicrobial and plant defence elicitor peptides have received attention on last decades as novel tools to combat bacterial plant diseases. We previously reported a library of peptide conjugates resulting from the combination of an antimicrobial peptide (, , or ) and a plant defence elicitor sequence (, , or ). From this library, we selected a set of 14 peptide conjugates including both highly and poorly active sequences and we performed a structure-activity relationship study by NMR and MD simulations. Analysis of their structure by NMR in 30% TFE-d and in zwitterionic DPC-d and anionic SDS-d micelles showed that the presence of an α-helix fragment together with a flexible random coil can be related to a high antibacterial activity and a low hemolysis. In contrast, the sequences with a rigid α-helix structure were low active and highly hemolytic. PRE-NMR experiments in presence of MnCl and 16-DSA revealed that the highly active peptides and interacted stronger with DPC-d micelles than the low active peptide . In the two former sequences this interaction took place through the α-helix region. From GaMD simulations of conducted in membranes composed of anionic DPPG lipids, after its electrostatic interaction, the peptide flipped and the hydrophobic residues were faced to the membrane triggering its insertion and also causing membrane thinning. Thus, the flexibility and moderate cationicity of seem to be crucial for its biological activity. These findings can help to establish the guidelines for future rational design of derivatives.

Rice blast disease, instigated by (), significantly impedes global rice production. Targeting the signaling protein, cAMP-Protein Kinase A (CPKA), which facilitates appressorium development and host penetration, this study explores the potential inhibitory effects of natural compounds. Virtual screening, molecular docking and text mining approaches were used to find the nimonol and curcumin that inhibit the CPKA protein. The MM-PBSA method was used to do the molecular dynamics (MD) simulation and the binding free energy analysis of the molecule. Their binding free energies (ΔG) of -78.81 kJ/mol and -117.65 kJ/mol, respectively, point to the potential efficacy of the CPKA-nimonol and CPKA-curcumin complexes as inhibitors. The inhibitory effects have been further verified by various MD analysis. This study emphasizes the need to conduct further study on the CPKA protein and gives important insights into the possibility of natural compounds as inhibitors.

Cancer sparks if the components of the cellular signaling network are aberrantly activated, leading to uncontrolled cell growth and proliferation. One of the most important players of this highly regulated network is the Wnt/β-catenin signaling, with a significant role in human health and disease. The critical co-receptor of this pathway, LRP6, is overexpressed in various cancer types and is a target for therapy. Therefore, understanding the details of the LRP6 structural activation mechanism is of tremendous importance. This research intended to compare the structural-dynamics features of the E3E4 functional domain of LRP6 induced by the activator Wnt3a and the inhibitor, Dkk1_C, compared with the receptor behavior in the apo-state. Using molecular docking, molecular dynamics simulation, and G_MMPBSA calculation, we characterized overlapping binding regions of Wnt3a and Dkk1_C on E3E4. Despite their overall similar interacting regions, Dkk1_C and Wnt induce remarkably different inter-blades hydrogen bonds, structural-dynamics behavior, and conformational energy landscape in E3E4. According to our findings, Dkk1_C stabilized the interaction. between BP3 blades 2-3, 3-4, and 4-5 and BP4 blades 1-6, 1-2, 2-3, and 3-4, aligned with apo-state. However, on the other hand, Wnt distinguishably destabilized the hydrogen bond networks of these blades. Our DCCM analysis also depicted a similar correlation pattern of apo and Dkk1-bound states, and dramatic differences in Wnt-bound state, with a specific enhancement of correlated movements in EGF4. These data provide atomistic-level clues of how natural regulators of Wnt signaling manipulate LRP6 dynamics and, therefore, guide the structure-based design of efficient artificial inhibitors/activators for the pathway.

The widespread use of glyphosate and the high dependence of the agricultural industry on this herbicide cause environmental pollution and pose a threat to living organisms. One of the appropriate solutions in sustainable agriculture to deal with pollution caused by glyphosate and its metabolites is creating a symbiotic relationship between plants and mycorrhizal fungi. Glomalin-related soil protein is a key protein for the bioremediation of glyphosate and its metabolite aminomethyl phosphonic acid in soil. This study uses homology modeling, molecular docking, and molecular dynamic simulation approaches to investigate the binding mechanism of glomalin-related soil protein from arbuscular mycorrhiza (GmHsp60) with glyphosate and its metabolite and the role of soil protein in the removal and sequestering of common agricultural soil pollutants. GmHsp60 protein structure was predicted by homology modeling, and the quality of the generated model was assessed. Then, the interaction between glyphosate and aminomethyl phosphonic acid and the modeled GmHsp60 protein was explored by molecular docking. Based on docking results, GmHsp60 has an efficient role in the bioremediation of glyphosate and aminomethyl phosphonic acid (-6.03 and -5.34 kcal/mol). Glyphosate forms three hydrogen bonds with Lys258, Gly262, and Glu58 of GmHsp60, and aminomethyl phosphonic acid forms three hydrogen bonds with Lys258, Gly261, and Gly262 of GmHsp60. In addition, the glyphosate's and its metabolite's stability was confirmed by molecular docking simulations and binding free energy calculations using MM/PBSA analysis. This study provides a molecular-level understanding of GmHsp60 expression and function for glyphosate bioremediation.